This proposal is directed at enhancing and maintaining fixation of total knee replacement (TKR) implants to the skeleton through a process known as bone ingrowth. In 1992, 199,000 primary total knee replacements were performed in the U.S. Of these, it has been estimated that 47% are "cementless," a type of implant in which fixation depends upon bone ingrowth into a porous surface. Two conditions known to inhibit initial fixation by bone ingrowth, lack of uniform contact between the implant and supporting bone and motion at the bone-implant interface, are inevitably present to some degree in cementless TKR. Recently, we have found (i) that transforming growth factor-beta/1 (TGF-beta/1), a known stimulator of bone repair, enhances bone ingrowth in a non-weight-bearing model and (ii) that bone morphogenetic protein-2 (BMP-2) retains its osteoinductive properties when applied to a porous-coated implant. TGF-beta enhances ongoing processes such as woven bone formation when delivered locally at freshly created sites of skeletal injury, whereas BMP works by inducing bone to form through a cartilaginous precursor. Thus, it is likely that TGF-beta will work well in situations where there is rigid fixation but gaps at the interface. However, the ability of TGF-beta to promote bone ingrowth in the presence of motion may be problematic. It seems likely that BMP would be a better means of promoting bone ingrowth in the presence of interface motion because of its different mechanism of action. Thus, the two hypotheses are directed at determining if treatment of the implant with either TGF-beta/1 or BMP-2 can enhance bone ingrowth and implant fixation in the presence of interface gaps and interface motion in a canine model of cementless TKR. Specifically, the dose-response curve for implants treated with each growth factor will be determined, followed by tests to assess the enhancing potential of these growth factors, using quantitative measures of implant fixation stability and bone ingrowth as the endpoints. The studies will help to determine in which situations application of growth factors to implants will be helpful for establishing fixation to the skeleton.